alpha-[(p-chlorophenyl)-alpha-phenyl]-4-pyridyl carbinol as a potentiating agent



United States Patent 3,010,873' a-[{p-CHLOROPI'IENYL)-ofiPHENYL1-4-PYREYL CARBINQL; AS Aj POTENTIATIN G AGENT Guido Cavaliini and Franco Ravenna, Milan; Italy, as-

I signors to Maggioni & C.S.p.A., Milan, Italy; an Italian omp y No Drawing. Filed Feb. 25; 1959, Ser; No. 795,366 Claims priority, application Italy Oct. 3, 1956' 20 Claims. (Cl. 167-65) This invention relates to novelcomposition and method of potentiating ataractic, analgesic, hypnotic, and myorelaxing drugs.

This application is a continuation-in-part of application more; treatments very often must be continued for long,

periods of time and thus, give rise to the danger of chronic toxicity. Another important object of the present invention is to provide nontoxic potentiatingcompounds'for the above listed drugs. The potentiating compounds of the invention not only are such as to exhibit-no unpleasant sideefiects when administered in conjunction with anyof the ataractic, analgesic, hypnotic and'myorelaxing drugs referred to above, but also are themselves inert and harmless substances if administered alone.

Among" the ataractic, analgesic, hypnotic, and myore laxing drugs liable to be potentiated according to the method of this invention-the following can be mentioned:

Barbiturates in general, such as-S-phenyl-S-ethyl-ba-rbituric (Phenobarbital) and S-ethyl-S-(l-methylbutyI)-'barbituric acids (Pentobarbita Opium alkaloids; such as morphine and total extracts of opium alkaloids (Pantopon);

Analgesic-spasmolytic drugs, such as l-alkyl-4-phenylpiperidine-4-alkyl (Pethidine) Ataraxics such as Meprobamate (2-n-propyl-l-,3- propanediol-dicarbamate), and Fenaglycodol 2-pchloro'phenyl-3 1nethyl 2,3 -butanediol;

Analgesics of 1tlie'lviethadone class such as 6 dimethylamino-4, 4-diphenyl-3-heptanone and derivativesthereof;

Skeletal-muscle relaxing, curare-like drugs, suchas tris-{diethylamino ethyl-hydroxy]-1,2,3-benZene-triiodoethylate [Gallamine and similar compounds;

Myorelaxing drugs, such as fMethocarbamol (3-0- niethoxyphenoxy-2-hydroxypropl-carbamate), and derivatives thereof.

illustrative of the potentiating ;'compounds which may be' used in performing themethod' and in forming the compositions accordingto the present invention are: a [(-prchlorophenyl) a-phenyH- l-pyridyl carbinol; and the nontoxic, phannacologically acceptable salts thereof.

carbonate andderivatives thereof ICE:

proven to? be valuable as an agent capable of potentiat ing' the actionofanalgesics, tranquilizers, sedatives" and'i hypnotics and; ingeneral, the neurot'r opic drugs acting? on the nervous centrahsystem: The above identified compound has also shown "a "markedpotenti'atingfiactioii" towards skeletal rnus'cle' loosening, curarelike' drugs," and myorelaxingdrugs' in general;

Thus, according to theinv'ention; we'provide a medicinal preparation comprising a centrally acting drug"sej-' lected' from the groupcon'sistin'g "of barbiturates, opium alkaloids; 1methyl-4=phenyl-piperidine 4-ethyl carbonate; 2 methyl2-n-propyl-1,3 propanediol-dicarbamate, 6- diinethylamino-4,4-diphenyl-3-heptanone and 2-p-chlorophenyl-3-methyl 2,3-butanediol, and w-- -[(p-chloro phenyl)-a-phenyl]-4-pyridyl-carbino1,- which acts as a potentiating compound capable of substantially increas ing the effectiveness of thecentra'lIy acting drug. 7 Also, according to the invention; we provide a Inedicinal preparation comprising a myorelaxin'g'drug selected from the group comprising tris-[diethylamino-ethylehydroxy] 1,2,3-benzene triiodoethylate and 3-o-methoxyphenoxy-Z-hydroxy-propyl-carbamate, e and their deriva tives, and ot-[(p-chlorophenyl)-u-phenyl]-4-pyridyl-+ cari binol, which acts as a potentiatingcompound capable of substantially increasing the myorelaxing effectiveness of said myorel'axing drug' i v a Our invention provides, moreover; a method of potentiating the 'ataractic, analgesic and l'fypnoticeffect of a centrally acting drug selected from the group'consisting of barbituratcs, opium alkaloids, Z-methyI Z-n ropyl-EI,3; propanediol dicarbamate, 1-alkyl- 1-pheny1-piperidine-4- alkyl carbonates, 6 dimethylamino-4,4-diphenyl-3-heptanone and 2-p-chlorophenyl-3-methyl-3,3i butanediol which comprises administering internally, for combined physiological action with said drug, a suitable dosage of a (p-chlorophenyl) -a-phenyl] -4-pyridyl-carbinol.

According to our said invention, a method is also provided for potentiating the'myorelaxing'effe'ct of a muscle relaxing drug selected from .the group comprising. tris- [die thylaminoethyl hydroxy] -1 ,2,3 -benzene' triiodoethyl ate and 3-o-methoxy-phenoxy-2-hydroxpropyl' 'carbiamate, and their derivatives, which comprises administeringin'ternally, .for combined physiological action-with said'myor'elaxing drug a suitable dosage-"of 'a-[--p-chlorophenyl) -a-phenyl] -.4-pyridylcarbine I The potentiating compound of the 'instantinvention may be prepared by a number of; differentv chemical:

W processes, for example byrefluxing 4-p-"chlorobenzjoyl 50" pyridine with an organic magnesium compound of the? structure XMgR wherein X is an atom of "a halogen having an atomic weight higher than 19-and R is -a mernber selected from the group consistingof analkyl radical having not more than Scarbon atoms, aphenyl radical, and a phenylalkyl radical having not niore'th an -11 carbon atoms, as disclosed in our application tor Letters Patent of the United States Serial No. 687,375, filed October 1, 1957, of which this application is acontinuanon-impart] I In the practical use of the potentiating compound of the invention it has been found expedient to administer the potentiating compound first, land in general from so'minutes' to '1 hour before administering are drug "whhse same obtained by administering the potentiating corn- 5 pound first.

Thus, the compositions of this invention may be advantageously employed in multiple doses and in timed delay tablets and the like. Due to the relative insolubility of the potentiating compound of the invention in aqueous 10 media they do not lend themselves to administration by injections so that the preferred form of administration ought to be one permitting the difiusion of the potentiating compound through the organism without the intermediary of liquidmedia. Thus, administration by tablets 15 and suppositories is preferred but this is not, of course, the only form of administration, since any other form which does not require solubilization of the potentiating compound is equally well adapted to the purpose.

As has been outlined hereinbefore, the potentiating 20 compound of the invention is itself harmless and an inert substance since the product is tolerated by animals (mice) in doses up to 3 gms. per kgm. body weight (acute tox- 4 icity), and for 40 days at the daily dose of 50 mgms. per kgm. body weight. The latter dose is at least 100 times the dosage required in order that an appreciable potentiating effect might be observed in the same animals.

Clinical tests have been carried out on human beings by administering the potentiating compound of the invention alone; no alteration in the morbid pattern of the patients thus treated has ever been observed.

Generally speaking, the selected potentiat-ing compound will be used in single doses of from about 10 to about 20 mgms, the daily dose being liable to vary from about 20 to about 100 mgms. The amount of potentiating compound will, of course, vary widely depending on the drug to be potentiated, the potentiating efiect desired and the nature of the disease being treated.

Also, the amount of the selected drug to be potentiated will vary widely depending on the physiological effect to be achieved. Generally speaking, it is desirable to employ from about the standard efiective therapeutic dose of the selected drug to about one-third the standard dose.

The following Table 1 reports practical examples of modes of practicing the method of the invention and making the medical preparations therefor.

Table 1 Ex. Syndrome or painful Treated Dosage, Potentiating Dosage, N o. affection under cases, Drug to he potentiated mgms. compound mgms. Observations treatment number 1- Insomnia, night- 4 B-phenyl fi-cthyl bar- 100 (daily)- a-Kp-chloro- 20 (dally) Normal sleep, for all 4 patients, of

mares. bituric acid (orally). phenyll-aprolonged duration as compared with phenyl] 4- that obtained with the barbiturate pyridylalone. carbinol. 2 Epileptic seizures. 7 do n do pattterntriizftairly ungltertd. d

' s ong po en ng so on owar s 3... Patients needing 20 33 52532 (m 20 the opium alkaloids is observed.

nurcosis before y do 20 (Single 'ldligggintigtinfg cortntpound has bleifn surgica operadi f t 1 5()( in 1 d a ere a ter e opium a o.- tions. so 10pm S g a 05G loids and before the tlopental.

. (mtmvenouslw dose) Very intensive anaesthetic client.

4... Patients having 19 l-methyl-i-phenyl 50 (single do- 20 The analgesic effect of the drug appears been subjected to piperidin-4-ethyl dose). to be markedly potentiated and lasts very painful surgicarbonate hydrofrom 6 to 16 hrs. cal operations. chloride (intramuscularly).

5- Patients having 15 6-dimethylamino-4,4-, (single do 20 (single The potentiated analgesic effect lasted been subjected to diphenyl-3-hepta dose). dose). from 10 hrs. to 22 hrs. and permitted very painful surnone hydrochloride e the patients to rest the night imgical operations (intramuscularly). mediately following the operation.

on the skeleton. 6 do 50 B-phenyl-fi-ethyl-bar- 30 (single ..-do .-d0 48 patients out of the 50 treated brilbituric acid (orally). dose). liantly responded to the treatment. The two nonresponsive cases were due to particular psychic conditions of the patients who successively become inmates of 3 Psychiatric 1 I Hospital. 7 do 10 5-ethyl-5-(l-methyl- 100 d0 20 A very sound sleep, lasting from 12 hrs. Y butyD-barbituric to a maximum of 22 hrs. is observed.

acid- (orally) 8- Patients having 10 None Nil ..do 2O Clinical pattern unaltered. Neither i been subjected to pharmacological action nor unvery painful surpleasant side effects are observed. gical operations p on the skeleton e (Control group).

9 Patients needing a 15 'lris-[diethylamlno' (single d0 20 The skeletal-muscle relaxing action or myorelaxing hydroxy]-1,2,3-bendose). the potentiated curare-like drug has treatment during zene triiodoethylate an intensity which is 3 times that progress of surgi- (a curate-like drug) afforded by the curare-like drug adcal operations. (intramuscularly). ministered alone.

1 A magirfd improvement 1the gteneral con ions, accompanie y at enus- Acutescmmphnima 5 tion of the hallucinations, delirious $82 59mm 3 Reserpine alkaloids 05 (daily) do 40 fantasies and restlessness. The pa- Chromc schizo. V 4 (orally). gangs, yet atterdthie first few days of mania ea ment nee e no restraining p means and became accessible to per- 7 suasive psychotherapy.

13..-- N euroses such as 2-methyl-2-n-propyl- 600 to 800 do 20 to Very remarkable improvements in the anxiety neuroses, 1,3-propanediol-dt- (daily). (daily). %of the treated cases. A notable hypochondrias, carbomate (Meproreduction of anxiety, restlessness and neurosthenic bamate) (orally). muscular strains was observed yet states with insomwithin the first week of 'treament. nia, neurasthenic The painful headaches and sexual states with neuroderangements, characteristic of these, vegetative neuroses, rapidly disappeared. The troubles. routine dosage of Meprobamate" p v r alone is from 800 to 1,600 mgms. daily.

14 Obsessional neuro- 12 ---.do -.d0 -d0.--.. 20 to 40 Very remarkable improvements in the ses. 80% of the treated cases. Disappearance of the sexual derangements and paiuiul headaches (nail-iu-thehead" feeling). Substantial relief from anxiety states.

piogsvs It is believed that' 'the cas'uistiyTporfd hereinbefore (199 cases) is-sufficient to illustrate thebest mode of practicing the rocess of are avenues; being it understoodth'at the" above examples are merelygillustrative and that it is "not'desired to be limited except -as set forth in the claims appended to this specification.

With particular respect to'the po tentiating eifect shown time, during which the righting reflex was abse'ntfo'llowing, theadministrationof -apotentia'ted and a" nonpotentiated myorelaxingdrug'respectively, was measured in mice.

several groups of mice, each group comprising 1Q animals, were injected with diiferent doses of methocarbamol, alone and potentiated with [u(p-chlorophenyl)-a-phenyl]- 4-pyridyl-carbin0l.

Table 2 Lack of righting reflex (r.r.), in minutes, methoearbamol alone, nonpotentiated Lack of righting reflex (r.r.), in

minutes, methooarbamol, potentiated with 60 mgm. of potentiating compound Num- Num- Nuin- Mgzn./ Mlnber of Mgm./ Minber of Number of kg. utes animals kg. utes animals ber of animals without without animals rlr. r.r.

250 0 0 250 48 10 10 10 325 27 3 325 146 l0 10 10 350 50 10 400 l0 10 10 400 70 1O 10 500 95 10 1 More than 4 hours.

The data tabulated above show that the righting reflex (r.r.) is absent for a relatively great length of time, when the myorelaxing drug is potentiated, whereas the nonpotentiated drug give times of absence of lighting reflex which are considerably shorter.

These preliminary pharmacological data are believed to be a suificient showing of the potentiating effect of oz-[ (p-chlorophenyl) -a-phenyl] -4-pyridy1-carbinol towards the myorelaxing activity of Methocarbamol.

What is claimed is:

1. A medicinal preparation comprising a centrally acting drug selected from the group consisting of barbiturates, opium alkaloids, 1-alkyl-4-phenyl-piperidine-4 alkyl carbonates, 2-methyl-2-n-propyl-1,3-propanediol-dicarbam-ate, 6-dimethylamino-4,4-diphenyl 3 heptanone, and 2-p-chlorophenyl-3-methyl-2,3-butanediol, and the tertiary alcohol a-[(p-chlorophenyl)-a-phenyl]-4-pyridyl carbinol which is normally inactive and capable of substantially increasing the eifectiveness of the selected centrally acting drug.

2. A medicinal preparation comprising a muscle relaxing drug selected from the group consisting of tris-(diethylamino-ethyl-hydroxy)-l,2,3-benzene triiodoethylate and 3-o-methoxy-phenoxy-Z-hydroxypropyl carbamate, and their derivatives, and the tertiary alcohol a-[(pchlorophenyD-a-phenyl]-4-pyridyl carbinol which is a normally inactive compound capable of substantially increasing the myorelax-ing effectiveness of said musclerelaxing drug.

3. The method of enhancing the ataractic, analgesic and hypnotic eifect of a centrally acting drug selected from the group consisting of barbiturates, opium alkaloids, l-alkyl-4-phenyl-piperidine-4-alkyl carbonates, 2- methyl-Z-n-propyl 1,3 propanediol dicarbamate, 6-dimethylamino-4,4-diphenyl-3-heptanone and Z-p-chlorophenyl3-methyl-2,3-butanediol, which comprises adminis't jering i' internally he tertiary agoner sup-emote phenyl -u-phnyl] -4-py 'ridyl carbinol; for combined physi logical action withsaid drug: v I

4. The method of enhancingihe muscle-relaxingiet comprising tris-(diethylamino-ethyl hydroxy) 1,2,3 b'en zne triiodoethylateand 3-o-methoxy-phenoxy 2-hydroxy propyl carbamate', and their derivatives; which comprises" administering internallytlie tertiary alcohol a- (p 'chloro phenyl) -a-phenyl]-4 -pyridyl carbinol, for combined physi'ologicalaction'with'said muscle-relaxing drug. v

5. A'medicinal' preparation comprising a. barbiturate; and the tertiary alcohol a-['(p-chlorophenyl) -'a-phenyl]-4- pyridyl carbinol which 'is normally inactive "and "capable of increasing the effectiveness of said barbiturate.

6. A medicinal preparation comprising a hypnotic drug consisting of "opium alkaloids, arid"the tertiary alcohol a[ (p chlorophenyl -u-phe'nyl] -4- pyri:dyl carbinol which is norrr'ially 'inac'tive;and capable 'of increasing the hyp-' notic efiect of said drug." v

7. A medicinal preparation comprising a neurotro ic drug consisting of a l-alkyl-4-phenyl-piperidine-4-alkyl carbonate, and the tertiary alcohol a-[(p-chl'orophenyl)- a-phenyl]-4-pyridyl carbinol which is normally inactive and capable of increasing the efiectiveness of said neurotropic drug.

8. A medicinal preparation comprising the neurotropic drug 2-methyl-2-n-propyl-1,3 propanediol dicarbamate, and the tertiary alcohol a-[(P-chlorophenyl)-u phenyl]-4- pyridyl carbinol which is normally inactive and capable of increasing the efiectiveness of said neurotropic drug.

9. A medicinal preparation comprising the analgesic drug 6-dimethylamino-4,4-diphenyl-3-heptanone, and the tertiary alcohol a-[(p chlorophenyl)-a-phenyl]-4-pyridyl carbinol which is normally inactive and capable of increasing the effectiveness of said analgesic drug.

10. A medicinal preparation comprising the neurotropic drog 2-p-chlorophenyl-3-methyl-2,3 butanediol, and the normally inactive tertiary alcohol a-[(p-chlorophenyl)-a-phenyl1-4-pyridyl carbinol which is capable of increasing the eifectiveness of said neurotropic drug.

11. A medicinal preparation comprising the musclerelaxing drug tris-(diethylamino-ethyl hydroxy) 1,2,3- benzene-tri-iodoethylate, and the normally inactive tertiary alcohol oc- (p-chlorophenyl) -a-phenyl] -4-pyridyl carbinol which is capable of increasing the effectiveness of said drug.

12. A medicinal preparation comprising the muscle-relaxing drug 3-0-methoxy-phenoxy-2-hydroxy-propyl-carbamate, and the normally inactive tertiary alcohol a-[(pchlorophenyD-u-phenyl]-4-pyridyl carbinol which is capable of increasing the efiectiveness of said drug.

13. The method of enhancing the hypnotic effect of a hypnotic barbiturate, which comprises administering internally the tertiary alcohol u-[(p-chlorophenyl)-uphenyll-4-pyridy1 carbinol for combined physiological action with the barbiturate.

14. The method of enhancing the efiectiveness of an hypnotic drug consisting of opium alkaloids, which comprises administering interally the tertiary alcohol 0t[(pchlorophenyD-ahenyl]-4-pyridyl carbinol for combined physiological action with said hypnotic drug.

15. The method of enhancing the effectiveness of an analgesic and spamolytic drug consisting of a l-a1kyl-4- phenyl-piperidine-4-alkyl-carbonate, which comprises administering internally the tertiary alcohol u-[(p-chlorophenyD-a-phenyl]-4-pyridyl carbinol for combined physiological action with said drug.

none, which comprises administering internally the ter-' 'binol for combined physiological action with said analgesic drug.

i 18. The method of enhancing the efiectiveness of the ataractic drug 2-p-chlorophenyl-3-methyl-2,3 butanediol, which comprises administering internally the tertiary alcohol-a -[(p-chlorophenyl)-a-phenyl]-4-pyridyl carbinol for combined physiological action with said ataractic drug.

19. The method of enhancing the effectiveness of the 1 muscle-relaxing drug tris (diethylaminoethyl-hydroxy) 1,2,3-benzene triiodoethylate, which comprises administering internally the tertiary alcohol a-[(p-chlorophenyl)- a phenyl]-4-pyridyl carbinol for combined physiological action with said muscle-relaxing drug. 7

20. The method of enhancing the effectiveness of the muscle-relaxing drug 3-o-methoxy-phenoxy-2-hydroxypropyl-carbamate, which comprises administering internally the tertiary alcohol a-{(p-chlorophenyl-a-phenyl]-4-py1'idyl carbinol for combined physiological action with said muscle-relaxing drug.

Sperber Mar. 27, 1956 Cislak May 29, 1956 OTHER REFERENCES Cohen: IAMA, Nov. 3, 1956, pages 948-950.

Collomb: JAMA, Dec. 29, 1956, page 1646.

Brown: J. Pharm. &. Exptl. Therap., October 1956, pagesl53l6l.

Wikler: The Relation of Psychiatry to Pharmacology, 1957, pages 46-47. a

Lac'obsen: I. Pharmacy and PharmacoL, May' 1958, pages 273-294.

-Goodman and Gilman: The Pharmacological Basis of 

1. A MEDICINAL PREPARATION COMPRISING A CENTRALLY ACTING DRUG SELECTED FROM THE GROUP CONSISTING OF BARBITURATES, OPIUM ALKALOIDS, 1-ALKYL-4-PHENYL-PIPERIDINE-4ALKYL CARBONATE, 2-METHYL-2-N-PROPYL--1,3-PROPANEDIOL-DICARBAMATE, 6-DIMETHYLAMINO-4,4-DIPHENYL-3-HEPTANONE, AND 2-P-CHLOROPHENYL-3-METHYL-2,3-BUTANEDIOL, AND THE TERIARY ALCOHOL A-((P-CHLOROPHENYL)-A-PHENYL)-4-PYRIDYL CARBINOL WHICH IS NORMALLY INACTIVE AND CAPABLE OF SUBSTANTIALLY INCREASING THE EFFECTIVENESS OF THE SELECTED CENTRALLY ACTING DRUG. 